Endocrine Program, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.
J Immunol. 2012 Mar 15;188(6):2583-91. doi: 10.4049/jimmunol.1102715. Epub 2012 Feb 3.
Prolonged subjection to unstable work or lighting schedules, particularly in rotating shift-workers, is associated with an increased risk of immune-related diseases, including several cancers. Consequences of chronic circadian disruption may also extend to the innate immune system to promote cancer growth, as NK cell function is modulated by circadian mechanisms and plays a key role in lysis of tumor cells. To determine if NK cell function is disrupted by a model of human shift-work and jet-lag, Fischer (344) rats were exposed to either a standard 12:12 light-dark cycle or a chronic shift-lag paradigm consisting of 10 repeated 6-h photic advances occurring every 2 d, followed by 5-7 d of constant darkness. This model resulted in considerable circadian disruption, as assessed by circadian running-wheel activity. NK cells were enriched from control and shifted animals, and gene, protein, and cytolytic activity assays were performed. Chronic shift-lag altered the circadian expression of clock genes, Per2 and Bmal1, and cytolytic factors, perforin and granzyme B, as well as the cytokine, IFN-γ. These alterations were correlated with suppressed circadian expression of NK cytolytic activity. Further, chronic shift-lag attenuated NK cell cytolytic activity under stimulated in vivo conditions, and promoted lung tumor growth following i.v. injection of MADB106 tumor cells. Together, these findings suggest chronic circadian disruption promotes tumor growth by altering the circadian rhythms of NK cell function.
长期处于不稳定的工作或光照时间表下，特别是轮班工作者，与免疫相关疾病的风险增加有关，包括多种癌症。慢性昼夜节律紊乱的后果也可能扩展到先天免疫系统，促进癌症生长，因为 NK 细胞功能受昼夜节律机制调节，并在肿瘤细胞溶解中发挥关键作用。为了确定 NK 细胞功能是否被人类轮班和时差模型所破坏，研究人员将 Fischer（344）大鼠暴露于标准的 12:12 光照-黑暗周期或由 10 个重复的 6 小时光刺激提前组成的慢性时差范式中，每 2 天发生一次，随后是 5-7 天的持续黑暗。该模型通过昼夜节律跑步轮活动进行评估，导致相当大的昼夜节律破坏。从对照和转移动物中富集 NK 细胞，并进行基因、蛋白和细胞溶解活性测定。慢性时差改变了时钟基因 Per2 和 Bmal1 的昼夜节律表达，以及细胞溶解因子穿孔素和颗粒酶 B，以及细胞因子 IFN-γ。这些变化与 NK 细胞细胞溶解活性的昼夜节律表达抑制有关。此外，慢性时差削弱了 NK 细胞在体内刺激条件下的细胞溶解活性，并促进了 MADB106 肿瘤细胞静脉注射后的肺肿瘤生长。总之，这些发现表明，慢性昼夜节律破坏通过改变 NK 细胞功能的昼夜节律来促进肿瘤生长。
